cerebral malaria severe complication of falciparum malaria mortality of 30-50% associated with...
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Disease Severity Pv Po Pm Pf Average (per mm3)
20,000 9,000 6,000 50,000-500,000
Maximum (per mm3)
50,000 30,000 20,000 2,500,000
Paroxysm Severity
moderate to severe
mild mild to
moderate severe
Duration Disease Infection
3-8 w 5-8 y
2-3 w 12-20 m
3-24 w >20 y
2-3 w 6-17 m
Anemia ++ + ++ ++++ Complications renal cerebral
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Cerebral Malaria•severe complication of falciparum malaria
• mortality of 30-50%•associated with sequestration in micro-vasculature of brain
•a diffuse encephalopathy with loss of consciousness• consciousness ranges from stupor to coma• unresponsive to pain, visual, and verbal stimuli• convulsions frequently observed• onset can be gradual or sudden
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Complications Associated with Falciparum Malaria
• cerebral malaria• anemia• hyperpyrexia• hypoglycemia • acidosis• GI and liver syndromes• pulmonary edema• blackwater fever• algid malaria (shock)
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Features Indicating Poor Prognosis in Severe Malaria• impaired consciousness• repeated convulsions• respiratory distress• shock• acidosis/hyperlactemia• hypoglycemia• jaundice or other liver malfunctions• renal impairment• high parasitemia (>500,000/mm3)
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• all erythrocytes invaded• Pv/Po = reticulocytes• Pm = senescent RBC
• up to 36 merozoites• sequestration of
infected erythrocytes • trophozoite and schizont
stages• primarily in brain, heart,
lungs, and gut• complications• immune evasion
Higher Parasitemias in Falciparum Malaria
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• avoidance of spleen• low oxygen tensions• better invasion
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P. falciparum expresses ‘knobs’ on the surface of infected erythrocytes. Knobs mediate cytoadherence to endothelial cells.
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Several Parasite Proteins Are Associated with Knobs
• KAHRP and PfEMP2 are believed to interact with the submembrane cytoskeleton of the host erythrocyte
• reorganization of the membrane skeleton may result in knob formation
• PfEMP1 crosses the erythrocyte membrane and is exposed on the surface
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• family of 40-50 var genes• conserved intracellular C-terminus
• acidic terminal segment (ATS)• binds cytoskeleton + KAHRP
• transmembrane domain• variable extracellular domain
composed of modules• 2-7 copies of Duffy-binding like
domains • 5 sequence types ()
• 1-2 cys-rich interdomain regions• all have DBL1 + CIDR
• participates in cytoadherence
PfEMP-1 Structure
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• CD36• Ig super-family
• ICAM-1• VCAM-1• PECAM-1
• E-selectin• thrombospondin• chondroitin sulfate A• hyaluronic acid
• Rosetting Receptors• CR-1• glycosaminoglycan• blood group A
Possible Host Receptors
Binding SitesDomain ReceptorCIDR CD36
DBL rosetting
DBL ICAM-1
DBL CSA
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SequestrationHypothesis
cytoadherence
cerebral ischemia
hypoxia, metabolic effects
coma
death
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Neurological Sequelae AmongSurvivors of Cerebral Malaria
at discharge 23.3%
at 1 month 8.6%
at 6 months 4.4%van Hansbroek et al (1997) J. Pediatrics 131:125
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Problems with Sequestration Hypothesis
• rapid reversibility• lack of ischemic damage• low levels of permanent
neurological damage• sequestration occurs in
non-cerebral malaria cases
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Cytokine Theoryexo-
antigens TNF +
IL-1 nitric
oxide coma,
death
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Cytokine Theory Problem• minimal lymphocyte infil-
tration or inflammation
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Severe falciparum malaria
• potentially high parasitemias• sequestration• complex (and not fully understood)
host-parasite interactions